Preprint Neuroinflammatory imaging markers in white matter: insights into the cerebral consequences of post-acute sequelae of COVID-19 PASC, 2024, Clouston +

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Neuroinflammatory imaging markers in white matter: insights into the cerebral consequences of post-acute sequelae of COVID-19 PASC
Sean Clouston; Chuan Huang; Jia Ying; Zennur Sekendiz; Minos Kritikos; Ashley Fontana; Lev Bangiyev; Benjamin Luft

Symptoms of coronavirus disease 2019 (COVID-19) can persist for months or years after infection, a condition called Post-Acute Sequelae of COVID-19 (PASC).

Whole-brain white matter and cortical gray matter health were assessed using multi-shell diffusion tensor imaging. Correlational tractography was utilized to dissect the nature and extent of white matter changes. In this study of 42 male essential workers, the most common symptoms of Neurological PASC (n = 24) included fatigue (n = 19) and headache (n = 17).

Participants with neurological PASC demonstrated alterations to whole-brain white matter health when compared to controls made up of uninfected, asymptomatic, or mildly infected controls (n = 18). Large differences were evident between PASC and controls in measures of fractional anisotropy (Cohen’s D=-0.54, P = 0.001) and cortical isotropic diffusion (Cohen’s D = 0.50, P = 0.002). Symptoms were associated with white matter fractional anisotropy (fatigue: rho = -0.62, P < 0.001; headache: rho = -0.66, P < 0.001), as well as nine other measures of white and gray matter health. Brain fog was associated with improved cerebral functioning including improved white matter isotropic diffusion and quantitative anisotropy.

This study identified changes across measures of white and gray matter connectivity, neuroinflammation, and cerebral atrophy that were interrelated and associated with differences in symptoms of PASC. These results provide insights into the long-term cerebral implications of COVID-19.

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Figure 2
Correlational tractography comparing participants with post-acute sequelae of coronavirus disease with controls. Tracts are shown when they are statistically significant as defined by having an estimated false ≥ discovery rate < 0.05 (T 1). Blue tracts are shown to indicate the presence of decreases in the outcome of interest, while red shows tracts where the outcome has increased. Each panel shows four different directional views of the brain, and panels differ by neuroimaging outcome: A) Fractional Anisotropy; B) Mean Diffusivity; C) Axial Diffusivity; D) Radial Diffusivity; E) Isotropic Diffusion.



Figure 3
Violin plots showing Core Fractional Anisotropy levels stratified by Acute Coronavirus disease, 2019, and post-acute sequelae of Coronavirus disease, 2019, characteristics. Nominal p-values, derived from multiple t-tests, are reported. Core FA: Core Fractional Anisotropy. Panels showing A) Acute COVID-19 severity, B) Case status (no COVID, acute COVID only, and post-acute sequelae of COVID-19), C) Grouped years since initial infection, D) duration of post-acute sequelae of COVID-19.



Figure 4
Scatter plots and trend lines showing associations between physical and cognitive functioning in participants with post-acute sequelae of Coronavirus disease, 2019.

 

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neurological PASC demonstrated alterations to whole-brain white matter health when compared to controls made up of uninfected, asymptomatic, or mildly infected controls

average age, education, and cognitive ability metrics were matched between PASC participants and controls, but PASC participants had more severe clinical disease and more variable symptoms during their acute infections.

individuals with PASC developed a range of common symptoms, with more than half of all PASC participants reporting persistent fatigue (n=19), either cough or shortness of breath (n=18), headache (n=17), joint or muscle pain (n=16), chest pain (n=14), fever (n=13), or either brain fog or loss of taste or smell (n=12).

We calculated fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) using diffusion tensor imaging

The model-free technique separates isotropic from anisotropic diffusion, thereby reducing partial volume effects and crossing ¦bers. This approach has been shown to have improved reliability against edema and crossing fibers. It allows the quantification of isotropic diffusion (ISO, isotropic value of the spin distribution function). Quantitative anisotropy (QA) was extracted as a local connectome fingerprint, and used in connectometry analyses.

Using correlational tractography, we elucidated the presence of widespread neuroinflammation, with findings indicative of symmetric axonal injury.

Elevated values of white matter MD, RD, and ISO coupled with diminished FA values and insignificant AD and QA changes observed in PASC patients are strongly suggestive of axonal injuries with neuroinflammation

Indeed, the robustness of the FA parameter, particularly the whole-brain white matter average FA value, in differentiating PASC from controls (AUC > 0.8) underscores its potential clinical significance.

Our results bridge the current knowledge gap by highlighting the pervasive inflammatory landscape for individuals with neurological PASC.

the presence of FA dysfunction, in particular, is associated with a wide array of neurological PASC symptoms including fever, headache, fatigue, and pain